Chronic alcoholism is a major health problem in the U.S. resulting in over $12 billion dollars in medical expenses each year. Alcohol-induced hepatic damage is responsible for the majority of the morbidity and mortality associated with chronic alcohol consumption. Liver cirrhosis ranks as the 6th most common cause of death in the U.S., with ethanol implicated as the causative etiologic agent in 41-95 percent of the cases. The disease progresses from fatty infiltration and inflammation to irreversible tissue damage, with liver transplantation ultimately the only recourse. Although chronic alcohol consumption results primarily in hepatic dysfunction, there are also strong links to vascular (stroke, hypertension) and pulmonary (acute respiratory distress syndrome) complications. Chronic ethanol consumption has been linked to increased production of reactive oxygen and nitrogen species and compromised antioxidant defense systems. However, there are no studies which systematically integrate the effects of chronic ethanol consumption to the generation of reactive radical species, nitration of purines, proteins and lipids, and the consequent alterations in hepatic, pulmonary, and vascular structure/function. The investigators hypothesize that chronic ethanol administration increases nitric oxide ( NO), superoxide (02-), and peroxynitrite (ONOO-) production, thus leading to nitration and oxidation of biomolecules and compromised tissue structure/function. They propose to utilize genetically defined mouse models to modulate oxidant generating enzymes (iNOS and AO/XO) and antioxidant defenses (CuZn SOD1) to gain mechanistic insight into the ethanol-induced nitration of biomolecules and alterations in vascular and tissue structure/function. The investigators will ultimately apply targeted pharmacological interventions to minimize the ethanol-induced injury. Specific Aims: 1. Define the contribution of NO, O2-, and ONOO- in nitration of biomolecules (purines, proteins and lipids) and impaired tissue and vascular structure/function following chronic ethanol administration. 2. Modulate NO and 02- production to (a) reveal mechanisms of oxidative injury to liver, lung and vasculature, and (b) attenuate tissue and vascular dysfunction associated with chronic ethanol consumption. 3. Utilize targeted pharmacologic interventions to minimize chronic ethanol-induced nitration of biomolecules (purine, protein, and lipid) and subsequent impairment of tissue and vascular structure/function.These observations will provide a foundation for understanding the interactions for understanding the interactions of superoxide with NO in hepatic, pulmonary, and vascular tissue injury resulting from chronic ethanol administration. Mechanistic insights gained from these studies will guide development of pharmacologic interventions to limit the detrimental effects of reactive species and decrease the morbidity and mortality associated with chronic alcohol consumption and serve as a prelude to human clinical trials.